1. Field of the Invention
The present invention relates to novel xcfx89-amino-xcex1-hydroxycarboxylic acid derivatives having integrin xcex1vxcex23 antagonistic activity and a pharmaceutical composition comprising as active ingredient at least one of said derivatives.
2. Description of Related Art
A signal transmission system is very important to organisms from the viewpoints of physiological significance, the regulation of gene expression and the like. It has been clarified that integrins, i.e., glycoprotein receptors which are involved in cell adhesion and penetrate cell membranes, are related, for example, to wound healing and hemostasis, phagocytosis, biophylaxis, and the construction of cytoskeletons and, in addition, as such are signal transfer molecules (Cell, 69, 11, (1992)). For this reason, in recent years, organic chemistry associated with integrins has suddenly become drawn attention from the viewpoint of pharmacology, as well as from the viewpoints of molecular biology and cell biology.
It is being elucidated that, while the conformation of integrins undergoes a dynamic and complicate change, integrins binds to various ligands to transmit signal in both intracellular and extracellular directions (Junichi Takagi et al., The 50th Annual Meeting of the Japan Society for Cell Biology, S5-1, 1997). T. A. Springer of Harvard Medical School has recently predicted that a certain activated integrin has a xcex2-propeller structure and binds to a ligand on the upper face of the xcex2-propeller (Proc. Natl. Acad. Sci. USA, 94, 65, 1997). This hypothesis was also supported by researchers in Japan (Atsushi Irie et al., The 50th Annual Meeting of the Japan Society for Cell Biology, S5-2, 1997), and three-dimensional analysis on a molecular level associated with the activation of integrins as well as binding between integrins and ligands and the like has been initiated in real earnest.
T. A. Springer et al. has recently substantiated a hypothesis regarding the xcex2-propeller domain by experimentation, and has suggested that the xcex2-propeller domain in integrin xcex1-subunit has important interaction with integrin xcex2-subunit (Proc. Natl. Acad. Sci. USA, 95, 4870, 1998).
Among others, integrin xcex1vxcex23 binds to various extracellular matrixes, that is, ligands deeply involved, for example, in biodynamics or the crisis of diseases, such as vitronectin, fibrinogen, fibronectin, osteopontin, thrombospondin, von Willebrand factors, and collagen, to form complexes. Accordingly, integrin xcex1vxcex23 is of special interest as a potential drug target (DN and P, 10, 456, 1997). In fact, xcex1vxcex23 is expressed in a large amount in B cells, macrophages, monocytes, smooth muscle, activated endothelial cells and the like. Further, xcex1vxcex23 is known not to be strongly expressed in endothelial cells in a resting stage, but to be highly activated in the course of growth and infiltration, that is, in vascularization, wound healing, and inflamed sites. Further, the correlation between the frequency of expression of xcex1vxcex23 and the increase in infiltration of cancer has been observed in various cancer cells. On the other hand, a group of researchers at Scripps Research Institute in U.S.A. have clarified by advanced computer-assisted video imaging microscopy that microvascular expression of xcex1vxcex23 is observed during experimental middle cerebral artery occlusion and reperfusion in a baboon as a model (Y. Okada et al., Am. J. Pathol., 149, 37, 1996).
As described above, relationship of cell species, which express integrin xcex1vxcex23 in vivo, with xcex1vxcex23 activation stage, biophylaxis mechanism and the like has led to an expectation of clinical application of molecules having integrin xcex1vxcex23 antagonistic activity in various fields. In fact, compounds having integrin xcex1vxcex23 antagonistic activity are intended to be used clinically, and the results of animal tests on compounds having xcex1vxcex23 antagonistic activity in a wide range of diseases have been reported (S. S. Srivatsa et al., The 69th Annual Meeting of American Heart Association, 0231, 1996 (DuPont-Merc); J. F. Gourvest et al., The 18th Annual Meeting of The American Society for Bone and Mineral Research, p228, 1996 (Roussel-Hoechst); S. B. Rodan et al., The 18th Annual Meeting of The American Society for Bone and Mineral Research, M430, 1996 (Merck); T. L. Yue et al., The 70th Annual Meeting of American Heart Association, 3733, 1997 (SmithKline Beecham); A. L. Racanelli et al., The 70th Annual Meeting of American Heart Association, 3734, 1997 (DuPont-Merc); M. Friedlander et al., Conference of American IBC, Sep. 11, 1997 (The Scripps Research Institute); W. S. Westlin, Conference of American IBC, Feb. 23, 1998 (Searle); M. W. Lark et al., The 2nd Joint Conference of The American Society for Bone and Mineral Research and International Bone and Mineral Society, T064, 1998 (SmithKline Beecham); R. K. Keenan et al., Bioorg. Med. Chem. Lett., 8, 3171, 1998 (SmithKline Beecham); C. P. Carron et al., Cancer Res., 58, 1930, 1998 (Searle); and W. H. Miller et al., Bioorg. Med. Chem. Lett., 9, 1807, 1999 (SmithKline Beecham)).
From the viewpoint of chemical structure, compounds having integrin xcex1vxcex23 antagonistic activity can be classified into antibodies, low-molecular peptide and compounds analogous thereto, and low-molecular organic compounds. All the antagonists are structurally related to the sequence of tripeptide RGD (arginine-glycine-aspartic acid) that are considered indispensable for recognition in the attachment of a ligand. Low-molecular peptides having antagonistic activity include disintegrins derived from venom of snakes and, in addition, cyclic peptides. One of them, GpenGRGDSPCA, has been reported to inhibit migration of smooth muscle and to block integrin xcex1vxcex23, thereby to actually inhibit neointima formation in rabbits (E. T. Choi et al., J. Vasc. Surg., 19, 125, 1994). Further, RGD-containing cyclic peptide G4120 inhibited neointima formation in hamsters (Circulation, 90, 2203 (1994)). Further, Scripps Research Institute has recently reported that cyclic peptides having xcex1vxcex23 antagonistic activity are promising novel therapeutic agents for rheumatic arthritis (C. M. Storgard et al., J. Clin. Invest., 103, 47 (1999)). On the other hand, cyclic peptides containing BTD designed by a xcex2-turn mimic have been proved to strongly bind to xcex1vxcex23 receptors (M. Goodman et al., Bioorg. Med. Chem. Lett., 7, 997, 1997).
Several methods are known for designing small molecules through the utilization of the amino acid sequence of interest (RGD being used here) as a clue (Gen Ojima et al., Journal of The Society of Synthetic Organic Chemistry, 52, 413 (1994); Toshio Furuya, Shin-Tanpakushitu Oyo Kogaku, Fujitec Corporation). A peptide mimesis for constructing a new molecule based on the backbone of a peptide chain is generally known in the art. The concept of a new de novo design focused on the chemical structure and spatial configuration of amino acid side chains has been introduced for the first time early in the 1990s (R. Hirschman et al., J. Am. Chem. Soc., 115, 12550 (1993)). An attempt to apply this approach to the design and synthesis of xcex1vxcex23 antagonists has already been initiated (K. C. Nicolaou et al., Tetrahedron, 53, 8751, 1997).
Up to now, small molecules having xcex1vxcex23 antagonistic activity are disclosed in WO 95/32710 (Merck); WO 96/37492 (Dupont-Merc); WO 97/01540 (SmithKline Beecham); WO 97/08145 (Searle Co.); WO 97/23451 (Merck); WO 97/23480 (Dupont-Merc); WO 97/24119 (SKB); WO 97/26250 (Merck); WO 97/33887 (Dupont-Merc); WO 97/36858 (Searle); WO 97/36859 (Searle); WO 97/36860 (Searle); WO 97/36861 (Searle); WO 97/36862 (Searle); WO 97/24336 (SmithKline Beecham); WO 97/37655 (Merck); WO 98/08840 (Merck); WO 98/18460 (Merck); WO 98/25892 (Lilly); WO 98/30542 (SmithKline Beecham); WO 98/31359 (Merck); WO 98/35949 (Merck); WO 98/43962 (Dupont-Merc); WO 98/46220 (Merck); WO 99/05107 (SmithKline Beecham); U.S. Pat. No. 5,843,906 (Searle); U.S. Pat. No. 5,852,210 (Searle); EP 796855 (Hoechst); EP 820988 (Hoechst); EP 820991 (Hoechst); EP 853084 (Hoechst); GB 2326609 (Merck); GB 2327672 (Merck); R. M. Keenan et al., J. Med. Chem., 40, 2289 (1997); J. W. Corbett et al., Bioorg. Med. Chem. Lett., 7, 1371 (1997); K. C. Nicolaou et al., Bioorg. Med. Chem., 6, 1185 (1998); R. M. Keenan, et al., Bioorg. Med. Chem. Lett., 8, 3165 (1998); A. R. Rockwell et al. Bioorg. Med. Chem. Lett., 9, 937 (1999); and R. M. Keenan et al., Bioorg. Med. Chem. Lett., 9, 1801 (1999).
However, low-molecular integrin xcex1vxcex23 antagonists having a hydroxyl group at the xcex1-position of the carboxylic acid have not yet been reported.
The present inventors have found that a certain group of derivatives have potent integrin xcex1vxcex23 antagonistic activity. The present inventors have also found that a certain group of derivatives have potent GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity. The present inventors have further found that these derivatives have excellent water solubility and do not substantially have pharmacological activity which is not involved in integrin xcex1vxcex23 directly.
Accordingly, an object of the present invention is to provide a compound having integrin xcex1vxcex23 antagonistic activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity and also having excellent water solubility.
Another object of the present invention is to provide a therapeutic agent for a disease selected from the group consisting of integrin xcex1vxcex23-mediated diseases and diseases where GP IIb/IIIa antagonistic activity and/or platelet aggregation inhibitory activity are therapeutically effective, and an agent for inhibiting platelet aggregation.
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
wherein
A represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which is optionally condensed with another saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic group, wherein the heterocyclic group and the bicyclic group are optionally substituted by C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, or aralkyl and the C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, and aralkyl groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom,
or a group represented by formula 
wherein
R1, R2, and R3, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or nitrile, or R1 and R2 may together form group xe2x80x94(CH2)ixe2x80x94, wherein i is 4 or 5, or group xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
D represents a bond;  greater than NR4 wherein R4 represents a hydrogen atom or C1-6 alkyl and this alkyl group is optionally substituted by phenyl optionally substituted by C1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;  greater than CR5R6 wherein R5 and R6 each independently represent a hydrogen atom or C1-6 alkyl and this alkyl group is optionally substituted by phenyl optionally substituted by C1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom; xe2x80x94Oxe2x80x94; or xe2x80x94Sxe2x80x94;
X and Z, which may be the same or different, represent CH or N;
R7 represents C1-6 alkyl, C1-6 alkoxy, a halogen atom, amino, nitro, hydroxyl, an oxygen atom, or cyano and the C1-6 alkyl and C1-6 alkoxy groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
R8 represents C1-6 alkyl, C1-6 alkoxy, a halogen atom, amino optionally substituted by one or two C1-6 alkyl groups, nitro, hydroxyl, an oxygen atom, or cyano and the C1-6 alkyl and C1-6 alkoxy groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
Q represents  greater than Cxe2x95x90O,  greater than CHR13, or  greater than CHOR13 wherein R13 represents a hydrogen atom or C1-6 alkyl;
R9 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or aralkyl and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
J represents a bond or alkylene having 1 to 3 carbon atoms wherein alkylene is optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
R10 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or acyl and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, and acyl groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, c1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
R11 represents a hydrogen atom, C1-6 alkyl, or aralkyl and the C1-6 alkyl and aralkyl groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom;
m is an integer of 0 to 5;
n is an integer of 0 to 4;
p is an integer of 1 to 3; and
q is an integer of 1 to 3.
The compounds according to the present invention are useful as therapeutic agents for integrin xcex1vxcex23-mediated diseases.
Compound
The terms xe2x80x9cC1-6 alkylxe2x80x9d and xe2x80x9cC1-6 alkoxyxe2x80x9d as used herein as a group or a part of a group mean straight chain, branched chain, or cyclic alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
The terms xe2x80x9cC2-6 alkenylxe2x80x9d and xe2x80x9cC2-6 alkynylxe2x80x9d as used herein as a group or a part of a group mean straight chain, branched chain, or cyclic alkenyl and alkynyl having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl.
Examples of C1-6 alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C2-6 alkenyl include allyl.
Examples of C2-6 alkynyl include 2-propynyl and ethynyl.
Examples of xe2x80x9csaturated or unsaturated five- to seven-membered carbocyclic groupsxe2x80x9d include phenyl.
The term xe2x80x9csaturated or unsaturated five- to seven-membered heterocyclic ringxe2x80x9d as used herein means a five- to seven-membered heterocyclic ring containing at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms, preferably a five- to seven-membered heterocyclic ring containing one nitrogen atom, more preferably a five- or six-membered heterocyclic ring containing one nitrogen atom. The term xe2x80x9chetero-atomxe2x80x9d used herein means an oxygen, nitrogen, or sulfur atom. Examples of saturated or unsaturated five- to seven-membered heterocyclic groups include pyrimidyl, 1,4,5,6-tetrahydropyrimidyl, imidazolyl, tetrahydro[1,3]diazepinyl, and imidazolidinyl.
The saturated or unsaturated heterocyclic group may be condensed with another saturated or unsaturated heterocyclic ring to form a bicyclic ring. Such condensed cyclic groups include benzimidazolyl, naphthyl, and azabenzimidazolyl, for example, imidazo[4,5-b]pyridyl.
The term xe2x80x9caralkylxe2x80x9d as used herein as a group or a part of a group means C1-6 alkyl, preferably C1-4 alkyl, substituted by a saturated or unsaturated five- to seven-membered carbocyclic group or heterocyclic group. Examples of aralkyl include benzyl and phenethyl.
The term xe2x80x9chalogen atomxe2x80x9d means a fluorine, chlorine, bromine, or iodine atom.
In preferred combinations of X with Z, X represents CH while Z represents N, or both X and Z represent N.
When D represents a bond, preferably, X represents N, and, more preferably, X represents N while Z represents N.
When D represents  greater than NR4, preferably, X represents CH, and, more preferably, X represents CH while Z represents N.
When D represents  greater than CR5R6, preferably, x represents N, and, more preferably, X represents N while Z represents N.
When D represents xe2x80x94Oxe2x80x94, preferably, X represents CH, and, more preferably, X represents CH while Z represents N.
When D represents xe2x80x94Sxe2x80x94, preferably, X represents CH, and, more preferably, X represents CH while Z represents N.
D preferably represents a bond or  greater than NR4.
The bicyclic heterocyclic group represented by A is preferably a nine- or ten-membered heterocyclic group, more preferably a nine- or ten-membered heterocyclic group containing two or three nitrogen atoms.
Preferably, A represents a group of the following formula: 
wherein
Het represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which is optionally condensed with another saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic group, wherein the heterocyclic group and the bicyclic group are optionally substituted by C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, or aralkyl and the C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, and aralkyl groups are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom.
More preferably, A represents a group of the following formula: 
wherein
R21 and R23, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, or aralkyl
R22 represents a hydrogen atom or C1-6 alkyl, or
R21 and R23 may together form
group xe2x80x94(CH2)4xe2x80x94,
group xe2x80x94(CH2)3xe2x80x94,
group xe2x80x94CHR24CH2CH2xe2x80x94 wherein R24 represents C1-6 alkyl, a halogen atom, or amino, the alkyl group is optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, hydroxyl, or a halogen atom and the amino group is optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or aralkyl,
group xe2x80x94CH2CHR24CH2xe2x80x94 wherein R24 is as defined above,
group xe2x80x94CH2CH2xe2x80x94,
group xe2x80x94CHR24CH2xe2x80x94 wherein R24 is as defined above,
group xe2x80x94CR25xe2x95x90CR26xe2x80x94 wherein R25 and R26, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, or R25 and R26 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CR24xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 wherein R24 is as defined above, xe2x80x94CHxe2x95x90CR24xe2x80x94CHxe2x95x90CHxe2x80x94 wherein R24 is as defined above, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, or
R21 and R23 may together form
xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x95x90CR24xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x95x90CHxe2x80x94CR24xe2x95x90CHxe2x80x94,
xe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, or
xe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, and
R22 may represent a single bond between R21 and the nitrogen atom attached to R21.
In the compound represented by formula (I), one or more hydrogen atoms in the following portion may be substituted by R7. 
When m is zero (0), R7 is absent. When m is 1, one hydrogen atom in the above portion is substituted by R7. When m is 2 or more, two or more hydrogen atoms in the above portion are substituted by R7. In this case, the substituents may be the same or different. When R7 represents an oxygen atom, the bond between the R7 and the above portion is a double bond. m is preferably an integer of 0 to 2.
In the compound represented by formula (I), one or more hydrogen atoms in the phenylene portion may be substituted by R8.
When n is zero (0), R8 is absent. When n is 1, one hydrogen atom in the phenylene portion is substituted by R8. When n is 2 or more, two or more hydrogen atoms in the phenylene portion are substituted by R8. In this case, the substituents may be the same or different. n is preferably an integer of 0 to 2.
Q preferably represents  greater than Cxe2x95x90O or  greater than CH2.
J preferably represents an optionally substituted methylene or ethylene chain.
R9 preferably represents a hydrogen atom, C1-6 alkyl (preferably methyl, propyl, or cyclopropylmethyl), or aralkyl (preferably benzyl or phenethyl).
R10 preferably represents a hydrogen atom, C1-6 alkyl, or acyl wherein C1-6 alkyl and acyl are optionally substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, aralkyl, amino, or hydroxyl.
R11 preferably represents a hydrogen atom, unsubstituted C1-6 alkyl, or unsubstituted aralkyl.
Preferred compounds represented by formula (I) are those wherein
A represents a group of formula 
wherein
R21, R22, and R23 are as defined above;
D represents a bond or  greater than NR4;
X represents N or CH;
Z represents N;
Q represents  greater than Cxe2x95x90O or  greater than CH2;
m and n are each an integer of 0 or 1;
R7 represents optionally substituted C1-6 alkyl, a halogen atom, or an oxygen atom;
R8 represents a halogen atom, nitro, optionally substituted amino, cyano, optionally substituted C1-6 alkyl, or optionally substituted C1-6 alkoxy;
R9 represents a hydrogen atom, optionally substituted C1-6 alkyl, or optionally substituted aralkyl;
J represents an optionally substituted methylene or ethylene chain;
R10 represents a hydrogen atom, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted aralkyl, or optionally substituted acyl;
R11 represents a hydrogen atom, optionally substituted C1-6 alkyl, or optionally substituted aralkyl; and
p and q are each 1 or 2.
Further, preferred compounds represented by formula (I) are those wherein
A represents a group of formula 
wherein
R21 and R23 both represent a hydrogen atom, or R21 and R23 together form
xe2x80x94CH2CH2CH2CH2xe2x80x94,
xe2x80x94CH2CH2CH2xe2x80x94,
xe2x80x94CH2CH2xe2x80x94,
xe2x80x94CHR24CH2CH2xe2x80x94 wherein R24 is as defined above,
xe2x80x94CH2CHR24CH2xe2x80x94 wherein R24 is as defined above,
xe2x80x94CHR24CH2xe2x80x94 wherein R24 is as defined above, or
xe2x80x94CR25xe2x95x90CR26xe2x80x94 wherein R25 and R26 both represent a hydrogen atom, or R25 and R26 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94;
R22 represents a hydrogen atom or optionally substituted C1-6 alkyl,
provided that, when R21 and R23 together form xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x95x90CR24xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x95x90CHxe2x80x94CR24xe2x95x90CHxe2x80x94, xe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, or xe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, R22 forms a bond;
D represents a bond or  greater than NR4;
X represents CH or N;
Z represents N;
m and n are each 0 or 1;
R7 represents C1-6 alkyl;
R8 represents a halogen atom;
Q represents  greater than Cxe2x95x90O;
R9 represents a hydrogen atom, optionally substituted C1-6 alkyl, optionally substituted C3-6alkenyl, or optionally substituted aralkyl;
J represents an optionally substituted methylene or ethylene chain;
R10 represents a hydrogen atom, optionally substituted C1-6 alkyl, optionally substituted C3-6 alkenyl, optionally substituted aralkyl, or optionally substituted acyl;
R11 represents a hydrogen atom, optionally substituted C1-6 alkyl, or optionally substituted aralkyl; and
p and q are each 1 or 2.
Particularly preferred compounds represented by formula (I) are the following compounds:
t-butyl(2S)-hydroxy-3-[4-{4-(pyrimidin-2-yl)piperazin-1-yl}benzoylamino]propionate;
(2S)-hydroxy-3-[4-{4-(pyrimidin-2-yl)piperazin-1-yl}benzoylamino]propionic acid;
t-butyl(2S)-hydroxy-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate;
t-butyl(2S)-t-butoxy-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate;
(2S)-hydroxy-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
(2S)-hydroxy-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
(2S)-acetoxy-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
t-butyl(2S)-t-butoxy-4-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]butyrate;
(2S)-hydroxy-4-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]butyric acid;
(2S)-hydroxy-4-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]butyric acid;
benzhydryl 3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2s)-hydroxypropionate;
t-butyl(2S)-t-butoxy-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate;
3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-hydroxypropionic acid; and
3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-hydroxypropionic acid.
The compounds according to the present invention may form pharmacologically acceptable salts thereof. Such salts include non-toxic salts. Preferred salts include: hydrohalogenic acid salts such as hydrochloride salts, hydrobromide salts, or hydroiodide salts; inorganic acid salts such as nitric acid salts, perchloric acid salts, sulfuric acid salts, or phosphoric acid salts; lower alkylsulfonic acid salts such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts; arylsulfonic acid salts such as benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acid salts such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, or maleic acid salts; amino acid salts such as glutamic acid salts or aspartic acid salts; alkali metal or alkaline earth metal salts such as sodium salts, potassium salts, and calcium salts; and organic alkali salts . such as pyridine salts or triethylamine salts.
The compounds according to the present invention may form solvates (for example, hydrates, alcoholates such as methanolate and ethanolate, and etherates such as tetrahydrofuran).
Production of Compounds
Compounds according to the present invention may be produced according to scheme 1. In the scheme, A, D, X, J, R7, R8, R9, R10, R11, m, n, p, and q are as defined above. 
A compound represented by formula (IV) can be prepared by hydrolyzing a carboxylic ester represented by formula (II), wherein R31 represents C1-6 alkyl or aralkyl, to give a compound represented by formula (II) wherein R31 represents a hydrogen atom and then reacting the compound thus obtained with a compound represented by formula (III) to form an amide bond. Specifically, the compound represented by formula (IV) can be prepared by hydrolyzing the free carboxyl group in the compound represented by formula (II), wherein R31 represents a hydrogen atom, with an alkali according to a conventional method and then reacting the compound thus obtained with the amine represented by formula (III) to perform condensation (step 1).
In the condensation reaction, a condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, may be used either solely or in combination with N-hydroxysuccinimide, 1-hydroxybenzotriazole or the like. Benzotriazol-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate may be used solely in the presence of a base. The combination of these reagents permits the desired condensation reaction to proceed with high efficiency. Preferably, from the viewpoint of optimizing the yield, 1 to 3 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or its free base is used in combination with 1 to 2 equivalents of 1-hydroxybenzotriazole, or alternatively, 1 to 2 equivalents of benzotriazol-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate may be used.
Reaction solvents usable in the condensation reaction include dimethylformamide, dioxane, tetrahydrofuran, and methylene chloride. Preferred are dimethylformamide and a mixed solvent composed of dimethylformamide and methylene chloride. The reaction may be carried out in a range of 0 to 80xc2x0 C., preferably in a range of 0 to 50xc2x0 C.
In the condensation reaction, a tertiary amine, such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, or triethylamine, may be added as an organic base from the viewpoint of improving the yield. Preferably, 2 to 5 equivalents of N-methylmorpholine or diisopropylethylamine is added.
The reaction proceeds without the addition of these organic bases. The addition of the organic bases, however, is preferred from the viewpoint of the yield.
Compounds represented by formula (IV) wherein A represents an optionally substituted pyrimidine ring may be if necessary reduced to the corresponding tetrahydropyrimidine.
Compounds represented by formula (IV) wherein  greater than Cxe2x95x90O bonded to the phenylene portion is  greater than CH2 may be produced by reductively converting the carboxylic ester represented by formula (II), wherein R31 represents C1-6 alkyl or aralkyl, to an aldehyde and then reductively reacting the aldehyde thus obtained with the amine represented by formula (III). The reaction may be carried out according to the method described in Example 46 (a production example) of WO 99/52872.
Compounds represented by formula (IV) produced by the reductive amination wherein R9 represents a group other than a hydrogen atom can also be produced by a reaction process other than the method described herein. Specifically, the above aldehyde may be reductively reacted with an amine of the following formula:
H2Nxe2x80x94Jxe2x80x94CH(OR10)COOR11xe2x80x83xe2x80x83(IIIxe2x80x2)
wherein R10, R11, and J are as defined in formula (I), to produce a compound represented by formula (V) wherein R9 represents a hydrogen atom. Thereafter, this compound may be reductively aminated to introduce alkyl, alkenyl, or aralkyl into R9. The introduction of alkyl, alkenyl, or aralkyl into R9 is not always carried out for the compound represented by formula (IV) in the scheme. That is, the introduction of alkyl, alkenyl, or aralkyl into R9 may be carried out for the compound represented by formula (V) in the scheme. The reaction may be carried out according to the method described in Example 49 of WO 99/52872.
Further, in this reaction, R11 in xe2x80x94COOR11 corresponding to the carboxylic ester portion in the amine may represent a hydrogen atom.
The amine represented by formula (III) used in step 1 may be generally synthesized from a commercially available conventional compound in a single or two steps. Specifically, the corresponding carboxylic ester can be prepared by treating xcfx89-amino-xcex1-hydoxycarboxylic acid with isobutene under proper reaction conditons, for example, in the presence of sulfuric acid. If necessary, the hydroxy group may be protected. Specifically, for example, 3-amino-(2S)-hydroxypropionic acid (L-isoserine) or 4-amino-(2S)-hydroxybutyric acid (AHBA) may be used as xcfx89-amino-xcex1-hydroxycarboxylic acid.
Protective groups of the carboxyl group include lower alkyl esters and aralkyl esters. For example, ethyl ester, t-butyl ester, and benzhydryl ester may be used.
In the esterification for the production of a t-butyl ester of 3-amino-(2S)-hydroxypropionic acid or 4-amino-(2S)-hydroxybutyric acid, a part of the hydroxyl group is sometimes t-butylated (etherified). In the condensation reaction in step 1, however, the hydroxyl group at the xcex1-position may be protected or may not be protected.
In the t-butylation of 3-amino-(2S)-hydroxypropionic acid or 4-amino-(2S)-hydroxybutyric acid, when a conventional method described, for example, in WO 95/32710 as such is applied, the yield of the t-butylation can be improved, for example, by properly selecting the reaction solvent, the stirring efficiency, and the type and amount of the acid catalyst.
The esterification for the production of a benzhydryl ester of 3-amino-(2S)-hydroxypropionic acid or 4-amino-(2S)-hydroxybutyric acid proceeds without posing the problem of yield. In this case, when the amino group is previously converted to an acid salt, for example, a p-toluenesulfonic acid salt, the yield can be improved. The reaction solvent is not particularly limited. The reaction reagent is preferably diphenyldiazomethane.
Ester derivatives of 3-amino-(2S)-hydroxypropionic acid or 4-amino-(2S)-hydroxybutyric acid and hydroxyl-protected derivatives thereof, wherein R9 represents a hydrogen atom, may be used in the condensation reaction in step 1. Alternatively, the amino group may be further modified followed by the use of the modified amino group in the condensation reaction. An example of chemical modification of the xcfx89-amino group is alkylation. The alkylation may be carried out according to the method described in WO 99/38849 or WO 99/52872.
In step 2, the compound represented by formula (V) may be prepared by converting the carboxylic ester portion (xe2x80x94COOR11) in the compound represented by formula (IV) to a free carboxyl group to produce, if necessary.
The carboxylic ester portion in the compound represented by formula (IV) may be converted to the contemplated free carboxyl group by a conventional method, for example, by hydrolysis with an alkali, hydrolysis with an acid, or reaction with an acid. The deesterification reaction may be achieved by a novel method without any restriction or limitation.
The compound represented by formula (IV) is orally administrable integrin xcex1vxcex23 antagonist and/or GP IIb/IIIa antagonist. Therefore, the step of converting the carboxylic ester to the free carboxyl group is not always necessary.
Compounds represented by formula (V) wherein A represents an optionally substituted a pyrimidine ring may be, if necessary, reduced to the corresponding tetrahydropyrimidine. The reduction may be carried out by a conventional method. Examples of reduction methods usable herein include catalytic reduction in the presence of a catalyst, such as palladium-carbon, ruthenium-carbon, rhodium-carbon, palladium oxide, platinum oxide, ruthenium oxide, rhodium platinum oxide complex, rhodium aluminum oxide complex, Raney nickel, or palladium black, and a reaction, for example, with metallic sodium or metallic lithium in liquid ammonia. Preferably, the reduction is carried out in an acidic solvent, for example, in acetic acid acidified with hydrochloric acid, in the presence of palladium-carbon with hydrogen under normal or applied pressure.
Compounds represented by formula (II) in scheme 1, wherein D represents  greater than NR4, may be produced by introducing group A into the free primary amine in the compound represented by formula (VI) 
wherein D represents  greater than NR4; R32 represents a protective group of amino; R33 represents C1-6 alkyl or aralkyl; and X, R7, R8, p, and q are as defined above. The Nxe2x80x94C bond between the compound represented by formula (VI) and the group A may be formed by reacting the compound represented by formula (VI) with a reagent, such as optionally modified or substituted 2-bromopyrimidine, modified or substituted 2-chlorobenzimidazole, or 2-methylthio-2-imidazoline, in the presence of a reaction solvent, such as dimethylformamide, dimethyl sulfoxide, sulfolane, pyridine, or methanol, preferably dimethylformamide, in a temperature range of 50 to 170xc2x0 C., preferably in a temperature range of 60 to 140xc2x0 C.
Reagents usable in this step is not limited to those recited herein, and any reagent may be used so far as a carbon atom attached to two nitrogen atoms finally combines with the nitrogen atom in the primary amine attached to a carbon atom in the piperidine derivative to form a single bond. Further, optimization of the kind of substrates used and reaction conditions permits the Nxe2x80x94C bond to be formed by reacting palladium having a valency of 0 (zero), a phosphine ligand, and a base. Furthermore, the Nxe2x80x94C bond may be formed in accordance with the method of Tetrahedron, 51(2), 353, 1995. The reaction may be carried out according to the method described, for example, in Intermediates 26, 27, 29, and 39 in WO 99/52872.
An organic base, such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, or triethylamine, is preferably added as an acid scavenger from the viewpoint of improving the yield. The addition of 2 to 10 equivalents of diisopropylethylamine is preferred.
The compound represented by formula (II) wherein R4 has been substituted may be prepared by conventional or reductive N-alkylation followed by the introduction of group A into the primary amino group in the compound represented by formula (VI) or by the introduction of group A into the primary amino group in the compound represented by formula (VI) followed by N-alkylation of the secondary amino group, if necessary. The reaction may be carried out according to the method described in Intermediate 30 in WO 99/52872.
The compound represented by formula (VI) may be produced by reacting a compound represented by formula (IX) 
wherein X, R7, R8, R33, p, and q are as defined above, with phthalimide together with an azo compound in a reaction solvent such as tetrahydrofuran, benzene, toluene, dioxane, or dimethylformamide, preferably tetrahydrofuran, in the presence of a trialkylphosphine, preferably tributylphosphine, at xe2x88x9240 to 100xc2x0 C., preferably xe2x88x9210 to 40xc2x0 C., followed by the removal of the phthaloyl group. Azo compounds include 1,1xe2x80x2-(azodicarbonyl)dipiperidine, diethyl azodicarboxylate, and 1,1xe2x80x2-azobis(N,N-dimethylformamide). Among them, 1,1xe2x80x2-(azodicarbonyl)dipiperidine is preferred.
Alternatively, the compound represented by formula (VI) may be produced by converting the hydroxyl group in the compound represented by formula (IX) to a leaving group, for example, a sulfonyloxy group such as a methanesulfonyloxy group, or a halogen atom such as a bromine atom, allowing sodium azide or a combination of hydrazoic acid with an azo compound to act on the leaving group to convert the leaving group to an azide group, and then reducing the azide group. The reaction may be carried out according to the method described, for example, in Intermediates 35, 36, 41, 42, 43, 47, 48, 49, and 58 in WO 99/52872.
The compound represented by formula (II) in scheme 1, wherein D represents  greater than CR5R6, may be produced, for example, by reacting 2-(chloromethyl)benzimidazole with ethyl 4-(piperazin-1-yl)benzoate in dimethyl sulfoxide in the presence of potassium carbonate at room temperature. This reaction may be carried out according to the method described in Examples 89 and 90 in WO 99/52872.
The compound represented by formula (II) in scheme 1, wherein D represents xe2x80x94Oxe2x80x94, may be produced by reacting the hydroxyl group in the compound represented by formula (IX) with a basic atomic group having an alkylsulfonyl group, that is, a compound corresponding to group A. This reaction may be carried out in accordance with the method described, for example, in Japanese Patent Laid-Open No. 97818/1993 and EP 468766A1.
The compound represented by formula (II) in scheme 1, wherein D represents xe2x80x94Sxe2x80x94, may be produced by halogenating the hydroxyl group in the compound represented by formula (IX) and reacting the halogen atom with a basic atomic group having group xe2x80x94SH, that is, a compound corresponding to group A. The reaction of the halogen atom with group xe2x80x94SH may be carried out in accordance with the method described, for example, in Res. Lab., Kohjin Co., Ltd., Japan Chem. Pharm. Bull. (1977), 25(10), 2624-37.
The compound represented by formula (II) in scheme 1, wherein D represents a bond, may be produced by introducing group A into a free secondary amine in a compound represented by formula (IXxe2x80x2) 
wherein X, R7, R8, R33, p, and q are as defined above.
The compound represented by formula (IX) and the compound represented by formula (IXxe2x80x2) may be produced according to the method described, for example, in WO 99/52872 and WO 99/38849.
The compounds according to the present invention may also be synthesized according to scheme 2. In this L; scheme, A, D, X, J, R7, R8, R9, R10, R11, m, n, p, and q are as defined above. 
A compound represented by formula (VII) may be produced by hydrolyzing a benzoic ester represented by formula (VI), wherein R33 represents C1-6 alkyl or aralkyl, to give a compound represented by formula (VI), wherein R33 represents a hydrogen atom and then reacting this compound with a compound represented by formula (III) to form an amide bond. More specifically, the compound represented by formula (VII) may be prepared by hydrolyzing the free carboxyl group in the compound represented by formula (VI), wherein R33 represents a hydrogen atom with an alkali according to a conventional method and then reacting the compound thus obtained with the amine represented by formula (III) to perform condensation (step 3). In the compound represented by formula (VII), R32 represents a protective group of amino. Protective groups of amino include Fmoc (9-fluorenylmethoxycarbonyl), t-butyloxycarbonyl, benzyloxycarbonyl, and p-methoxybenzyloxycarbonyl. Preferred is t-butyloxycarbonyl.
Next, the compound represented by formula (V) can be prepared by removing the protective group in the piperidine derivative portion, introducing a basic atomic group corresponding to group A, for example, pyrimidine, benzimidazole, or amidino, into the deprotected primary amine, and then, if necessary, converting the carboxylic ester portion to a free carboxyl group (step 4). The reaction may be carried out according to Intermediates 20, 21, and 22 and Examples 21 and 22 in WO 99/52872.
If necessary, the carboxylic ester portion (xe2x80x94COOR11) in the compound represented by formula (VIII) may be converted to a free carboxyl group to produce the compound represented by formula (V).
The compound represented by formula (I), wherein X represents N and Z represents CH, may be produced from 4-bromobenzyl alcohol with the hydroxyl group being protected by the method described in WO 94/12181. Specifically, a phenylpiperidine derivative corresponding to formula (IX) can be produced by reacting lithiumized 4-bromobenzyl alcohol (with the hydroxyl group being protected) with N-Boc-4-piperidone to give a phenylpiperidine derivative, reductively removing the formed hydroxyl group, deprotecting the protected hydroxyl group, esterifying the deprotected hydroxyl group, and removing the Boc group. The compound represented by formula (I), wherein X represents N and Z represents CH, may be produced from the phenylpiperidine derivative according to scheme 1.
According to the production process of the present invention, the compounds according to the present invention can be efficiently synthesized by building block synthesis. Specifically, the starting material for the production of intermediates 1, 2, 3, 4, and 5 is L-isoserine or AHBA which is a starting material for commercially available semisynthetic aminoglycoside antibiotics, for example, isepamycin or arbekacin, and, thus, the efficient production process and purification process have already been established. Therefore, the production process according to the present invention advantageously comprises reliable steps.
Further, the production process according to the present invention is also advantageous in that the synthesis route is widely used. Since a hydroxyl group or a protected or modified hydroxyl group is located at the xcex1-position on the C-terminal side of the compound according to the present invention, the compound according to the present invention is different from low-molecular integrin xcex1vxcex23 antagonist having sulfonamide at their xcex1-position which has been reported, in reactivity. Specifically, in the building block on the C-terminal side which is located downstream of the synthesis route (in the present invention, for example, after the L-isoserine derivative has been bonded to the compound represented by formula (VI)), various reactions may be carried out under severe conditions, for example, after the deprotection of R31 in the compound represented by formula (VII) in the scheme. This is because a highly reactive functional group, such as a sulfonamide group, is absent in the molecule. Specifically, regarding the compound after the removal of R31 from the compound represented by formula (VII), the amino group preferentially reacts in a usual reaction, and, thus, excellent selectivity in chemical conversion to the compound represented by formula (V), as well as various chemical conversions can be expected. For this reason, the synthesis of integrin xcex1vxcex23 antagonist using the amine represented by formula (III) can be applied to the production of the compounds according to the present invention and, in addition, to the production of all of integrin xcex1vxcex23 antagonists using the amine represented by formula (III).
In the synthesis of the compound according to the present invention, for example, in scheme 1, an amino bond was first formed and the optionally substituted pyrimidine ring in the compound represented by the formula (V) was then reduced. Alternatively, in the compound represented by formula (II), the basic atomic group bonded to the primary amino group in the piperidine derivative, for example, the optionally substituted pyrimidine ring, may be reduced followed by the reaction for the formation of the amide bond.
In the compounds represented by formulae (IV) and (V) in the scheme, the atomic group, which has already been constructed in the molecule, for example, R7, R8, R9, and R10, may be if necessary further converted.
Use of Compounds/pharmaceutical Composition
The compounds according to the present invention have potent integrin xcex1vxcex23 antagonistic activity, as demonstrated in Pharmacological Test Example 1. Accordingly, the compounds according to the present invention can be used in the treatment of integrin xcex1vxcex23-mediated diseases. The integrin xcex1vxcex23 mediates cardiovascular diseases such as acute myocardial infarction, neointima formation hypertrophy, restenosis after PTCA/stent operation, unstable angina, arteria coronary syndrome, angina pectoris after PTCA/stent operation, arterial sclerosis, particularly atherosclerosis; angiogenesis-related diseases such as diabetic retinopathy, diabetic vascular complication, or vascular grafting; cerebrovascular diseases such as cerebral infarction; cancers such as solid tumors or metastasis thereof, immunological diseases such as arthritis, particularly rheumatic arthritis; and osteopathy such as osteoporosis, hypercalcemia, periodontitis, hyperparathyroidism, periarticular sore, or Paget""s diseases (DN and P, 10 (8), 456 (1997)).
Further, as described in Pharmacological Test Example 2, the compounds according to the present invention have GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity. Therefore, the compounds according to the present invention can be used in the treatment of diseases where GP IIb/IIIa antagonism and the inhibition of human platelet aggregation are therapeutically effective. More specifically, the compounds according to the present invention can be used in the treatment of platelet thrombosis and thromboembolism during and after the treatment of thrombolysis and after angioplasty of coronary artery and other arteries and after bypassing of coronary artery, the improvement of peripheral circulating blood stream, and the inhibition of blood clotting during extracorporeal circulation. Furthermore, the compounds according to the present invention can be used in the treatment of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (Gendai Iryo, 29, (11), 2753 (1997)).
The compounds according to the present invention have potent integrin xcex1vxcex23 antagonistic activity and, at the same time, are highly soluble in water. Therefore, the compounds according to the present invention are advantageously suitable for intraveneous injection in the acute phase, intravenous drip infusion in the acute phase, and eye drop administration.
Further, the compounds according to the present invention have advantageously substantially no side effect, that is, have substantially no pharmacological activity which is not involved in integrin xcex1vxcex23 directly.
The compounds according to the present invention and pharmacologically acceptable salts and solvates thereof can be administered orally or parenterally by administration routes, for example, inhalation administration, rhinenchysis, instillation, subcutaneous administration, intravenous injection, intravenous drip infusion, intramuscular injection, rectal administration, or percutaneous administration, and thus may be formed into appropriate various dosage forms depending on oral or parenteral administration routes and administered to human and non-human animals.
The compounds according to the present invention may be formulated into, for example, oral preparation, such as tablets, capsules, chewable preparations, granules, powders, pills, particulates, troches, syrups, emulsions, suspensions, or solutions; liquids for external use such as inhalants, nasal drops, or eye drops; patches; injections such as intravenous injections, intramuscular injections, or intravenous drip infusions; preparations for rectal administrations; oleaginous suppositories; water-soluble suppositories; and liniments such as ointments depending upon applications thereof. Further, liquid preparations, such as injections or drops, may be provided, for example, as a lyophilized powdery pharmaceutical composition, which may be dissolved or suspended in water or other suitable vehicle, for example, physiological saline, glucose infusion, or buffer solution, before use.
These various preparations may be prepared by conventional methods with commonly used components, for example, excipients, extenders, binders, humidifiers, disintegrants, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, antiseptics, flavoring agents, analgesic agents, stabilizers and the like. Non-toxic additives usable herein include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, olive oil, propylene glycol, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, ascorbic acid, and cyclodextrins.
The dose of the compound according to the present invention in the medicament may vary depending on the dosage form. The dose is, however, generally 1.0 to 100% by weight, preferably 1.0 to 60% by weight, based on the whole composition.
Regarding the pharmaceuticals according to the present invention, the dose and the number of times of administration are not particularly limited, and may be appropriately determined depending on, for example, the purpose of treatment or prevention, the type of diseases, the age, weight, and severity of condition of patients. The dose for the treatment and prevention of coronary diseases and the like may be appropriately determined depending on, for example, the dosage route and the age, sex and severity of condition of patients, and the active ingredient may be administered usually in an amount of about 0.1 to 2,000 mg, preferably about 5 to 400 mg per day per adult. This dose may be administered at a time daily, divided doses of several times daily, or at a time every several days.